rs9986447

Positions:

• chr6-42975041-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000287.4(PEX6):​c.883-3T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.421 in 1,609,494 control chromosomes in the GnomAD database, including 148,312 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (10783 hom., cov: 31)
  • Exomes 𝑓: 0.43 (137529 hom.)
• Consequence: PEX6 NM_000287.4 splice_region, intron
• Scores: Splicing: ADA: 0.0002058
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.428

Genes affected

PEX6 (HGNC:8859): (peroxisomal biogenesis factor 6) This gene encodes a member of the AAA (ATPases associated with diverse cellular activities) family of ATPases. This member is a predominantly cytoplasmic protein, which plays a direct role in peroxisomal protein import and is required for PTS1 (peroxisomal targeting signal 1, a C-terminal tripeptide of the sequence ser-lys-leu) receptor activity. Mutations in this gene cause peroxisome biogenesis disorders of complementation group 4 and complementation group 6. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]

PEX6 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 6-42975041-A-G is Benign according to our data. Variant chr6-42975041-A-G is described in ClinVar as [Benign]. Clinvar id is 92791.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-42975041-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.449 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PEX6	NM_000287.4	c.883-3T>C		splice_region_variant, intron_variant		ENST00000304611.13	NP_000278.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PEX6	ENST00000304611.13	c.883-3T>C		splice_region_variant, intron_variant		1	NM_000287.4	ENSP00000303511.8
PEX6	ENST00000244546.4	c.883-3T>C		splice_region_variant, intron_variant		1		ENSP00000244546.4

Frequencies

GnomAD3 genomes AF: 0.362 AC: 54812 AN: 151618 Hom.: 10782 Cov.: 31

Gnomad AFR AF: 0.230

Gnomad AMI AF: 0.583

Gnomad AMR AF: 0.324

Gnomad ASJ AF: 0.408

Gnomad EAS AF: 0.104

Gnomad SAS AF: 0.403

Gnomad FIN AF: 0.405

Gnomad MID AF: 0.396

Gnomad NFE AF: 0.453

Gnomad OTH AF: 0.383

GnomAD3 exomes AF: 0.373 AC: 93610 AN: 251010 Hom.: 19174 AF XY: 0.387 AC XY: 52530 AN XY: 135698

Gnomad AFR exome AF: 0.228

Gnomad AMR exome AF: 0.252

Gnomad ASJ exome AF: 0.414

Gnomad EAS exome AF: 0.105

Gnomad SAS exome AF: 0.424

Gnomad FIN exome AF: 0.402

Gnomad NFE exome AF: 0.449

Gnomad OTH exome AF: 0.409

GnomAD4 exome AF: 0.427 AC: 622873 AN: 1457760 Hom.: 137529 Cov.: 34 AF XY: 0.430 AC XY: 311688 AN XY: 725384

Gnomad4 AFR exome AF: 0.224

Gnomad4 AMR exome AF: 0.264

Gnomad4 ASJ exome AF: 0.413

Gnomad4 EAS exome AF: 0.125

Gnomad4 SAS exome AF: 0.432

Gnomad4 FIN exome AF: 0.394

Gnomad4 NFE exome AF: 0.453

Gnomad4 OTH exome AF: 0.408

GnomAD4 genome AF: 0.361 AC: 54841 AN: 151734 Hom.: 10783 Cov.: 31 AF XY: 0.358 AC XY: 26570 AN XY: 74154

Gnomad4 AFR AF: 0.230

Gnomad4 AMR AF: 0.324

Gnomad4 ASJ AF: 0.408

Gnomad4 EAS AF: 0.105

Gnomad4 SAS AF: 0.404

Gnomad4 FIN AF: 0.405

Gnomad4 NFE AF: 0.453

Gnomad4 OTH AF: 0.381

Alfa AF: 0.400 Hom.: 6878

Bravo AF: 0.346

Asia WGS AF: 0.250 AC: 870 AN: 3478

EpiCase AF: 0.457

EpiControl AF: 0.459

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 10, 2016	Variant summary: The PEX6 c.883-3T>C variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a polymorphism outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 45827/121356 control chromosomes (9493 homozygotes) at a frequency of 0.3776245, which greatly exceeds the estimated maximal expected allele frequency of a pathogenic PEX6 variant (0.0019365), indicating that this variant is a benign polymorphism. Multiple clinical labs have classified the variant as benign. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 07, 2018	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 23, 2013	- -

Peroxisome biogenesis disorder 4A (Zellweger) Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Peroxisome biogenesis disorder 4A (Zellweger);C3553937:Peroxisome biogenesis disorder 4B;C4225267:Heimler syndrome 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 11, 2021

- -

Zellweger spectrum disorders Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Heimler syndrome 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Peroxisome biogenesis disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Peroxisome biogenesis disorder 4B Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	8.3
DANN	Benign	0.80

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00021
dbscSNV1_RF	Benign	0.016
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs9986447; hg19: chr6-42942779; COSMIC: COSV55103559;